NF-κB p65 repression by the sesquiterpene lactone, Helenalin, contributes to the induction of autophagy cell death

BMC Complementary and Alternative Medicine

Research Article

Kandhadayar Gopalan Srinivasan¹  Hong Shuang Zhu²  Nung Ky²  Yan Zhao²  Chuan Bian Lim²  Jinming Li²  XiaoLing Feng³  Mohamed Sabry Hamza⁴  Pan You Fu⁵ 

[1] 1stBASE Pte Ltd., 41 Singapore Science Park II, The Gemini, 117610, Singapore, Singapore;Division of Chemical Biology and Biotechnology, School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore, Singapore;HeiLongJiang University of Chinese Medicine, Harbin, People’s Republic of China;MSD, Translational Medicine Research Center, 8 Biomedical Grove, #04-01/-05 & #05-01/05, Neuros Building, 138665, Singapore, Singapore;National Cancer Centre of Singapore, NCCS-VARI Translational Research Laboratory, #501, Level 5, 11 Hospital Drive, 169610, Singapore, Singapore;

关键词: Helenalin or Hele(Helenalin);    Autophagy;    Caspase;    NF-κB;    Atg12 and LC3-B;   

DOI  :  10.1186/1472-6882-12-93

 received in 2012-01-20, accepted in 2012-07-11,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundNumerous studies have demonstrated that autophagy plays a vital role in maintaining cellular homeostasis. Interestingly, several anticancer agents were found to exert their anticancer effects by triggering autophagy. Emerging data suggest that autophagy represents a novel mechanism that can be exploited for therapeutic benefit. Pharmacologically active natural compounds such as those from marine, terrestrial plants and animals represent a promising resource for novel anticancer drugs. There are several prominent examples from the past proving the success of natural products and derivatives exhibiting anticancer activity. Helenalin, a sesquiterpene lactone has been demonstrated to have potent anti-inflammatory and antitumor activity. Albeit previous studies demonstrating helenalin’s multi modal action on cellular proliferative and apoptosis, the mechanisms underlying its action are largely unexplained.MethodsTo deduce the mechanistic action of helenalin, cancer cells were treated with the drug at various concentrations and time intervals. Using western blot, FACS analysis, overexpression and knockdown studies, cellular signaling pathways were interrogated focusing on apoptosis and autophagy markers.ResultsWe show here that helenalin induces sub-G1 arrest, apoptosis, caspase cleavage and increases the levels of the autophagic markers. Suppression of caspase cleavage by the pan caspase inhibitor, Z-VAD-fmk, suppressed induction of LC3-B and Atg12 and reduced autophagic cell death, indicating caspase activity was essential for autophagic cell death induced by helenalin. Additionally, helenalin suppressed NF-κB p65 expression in a dose and time dependent manner. Exogenous overexpression of p65 was accompanied by reduced levels of cell death whereas siRNA mediated suppression led to augmented levels of caspase cleavage, autophagic cell death markers and increased cell death.ConclusionsTaken together, these results show that helenalin mediated autophagic cell death entails inhibition of NF-κB p65, thus providing a promising approach for the treatment of cancers with aberrant activation of the NF-κB pathway.

【 授权许可】

Unknown   
© Lim et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.